Evaluation of the effect of Exercise Trainings and CGRP receptor antagonist (BIBN 4096) on mitochondrial dynamic in the hippocampus of male Wistar rats.

BACKGROUND: Exercise training showed beneficial effects on brain. The purpose of the present study is to evaluate the effect of six weeks of high-intensity interval training (HIIT) and Endurance training (ET) with calcitonin gene-related peptide (CGRP) receptor antagonist on the expression of genes involved in mitochondrial dynamics and apoptosis in hippocampal tissue of male Wistar rats. METHODS: In this study, forty-two healthymale Wistar rats (8-week) were randomly divided into 6 groups (n = 7) as follow; 1) Control; 2) HIIT which performed 6 weeks of HIIT; 3) ET which performed 6 weeks of endurance training; 4) CGRPi received 10 mg/kg CGRP receptor antagonist every day at the last 2 weeks; 5) CGRPi-HIIT performed HIIT and received CGRP receptor antagonist; 6) CGRPi-ET performed ET and received CGRP receptor antagonist. Real-time PCR (2-ΔΔCT) and western blotting were employedto measure the expression of genes and protein, respectively. RESULTS: HIIT and ET significantly increased Bcl-2, Pgc-1α, Sirt3, and Nrf-1 gene expression in the hippocampal tissue (p < 0.05, p < 0.01, p < 0.01, and p < 0.001, respectively). ET-CGRPi and HIIT-CGRPi significantly increased Sirt3, Pgc-1α, and Nrf-1 gene expression compared to the control group (p < 0.05, p < 0.01, and p < 0.05, respectively). CONCLUSION: ET and HIIT-induced physiological alterations in the hippocampus. In fact, this modulation showed protective properties in the hippocampusvia up regulation of Bcl-2, Pgc-1α, Nrf-1, and Sirt3 gene expression. CGRPi did not cause gene or protein changes harmful to mitochondrial dynamic balance and apoptosis in the hippocampus of rats.

Metabolic Regulation of T cell Activity: Implications for Metabolic-Based T-cell Therapies for Cancer

Immunometabolism is an emerging field in tumor immunotherapy. Understanding the metabolic competition for access to the limited nutrients between tumor cells and immune cells can reveal the complexity of the tumor microenvironment and help develop new therapeutic approaches for cancer. Recent studies have focused on modifying the function of immune cells by manipulating their metabolic pathways. Besides, identifying metabolic events, which affect the function of immune cells leads to new therapeutic opportunities for treatment of inflammatory diseases and immune-related conditions. According to the literature, metabolic pathway such as glycolysis, tricarboxylic acid cycle, and fatty acid metabolism, significantly influence the survival, proliferation, activation, and function of immune cells and thus regulate immune responses. In this paper, we reviewed the role of metabolic processes and major signaling pathways involving in T-cell regulation and T-cell responses against tumor cells. Moreover, we summarized the new therapeutics suggested to enhance anti-tumor activity of T cells through manipulating metabolic pathways.

Adaptation of the standardized plant analysis-risk human reliability analysis technique for the surgical setting: expert judgment approach.

Objectives. Application of human reliability analysis (HRA) techniques originally developed for industrial settings to the healthcare sector may be controversial in terms of reliability and methodological level. The aim of the present study was to adapt a standardized plant analysis risk-human reliability analysis (SPAR-H) technique for application in surgical settings through suggesting more context-specific definitions for performance shaping factors (PSFs), designing precise levels and elicitation of multipliers through a domain expert judgment approach. Methods. A ratio magnitude estimation approach was used for carrying out domain expert judgment for multiplier elicitation. Experts from four teaching hospitals participated in the present study. Intra-class correlation was used in order to examine the inter-rater reliability of the estimated multipliers for each level of diagnosis and action task type. Results. Available time, threat stress, task complexity, experience/training, procedures, working conditions, human-machine interface, fatigue and teamwork were the nine suggested PSFs for the adapted SPAR-H technique. Conclusion. Context-specific definitions of the PSFs can enhance the reliability of human error probability assessments. Eventually, it could be concluded that multiplier elicitation through domain expert judgment is an efficient approach for adaptation of the HRA techniques for application in specific contexts.

Effects of green light-emitting diode irradiation on neural differentiation of human umbilical cord matrix-derived mesenchymal cells; Involvement of MAPK pathway.

Alteration of the proliferation rate and differentiation of mesenchymal stem cells (MSCs) into various lineages, including neural cells, by light emitting diodes (LEDs) irradiation has received considerable attention in recent years. Human umbilical cord matrix-derived mesenchymal cells (hUCMs) are an accessible source of adult stem cells with appropriate characteristics that make them ideal tools for stem cell researches, cell therapy procedures and regenerative medicine. The aim of the present study was to investigate the effects of green LED irradiation, retinoic acid (RA) and their combination on the differentiation of hUCMs into neural lineage as well as the mechanisms involved. Exposure of hUCMs to green LED (530 nm, 1.59 J/cm2) with or without retinoic acid (RA) treatment, significantly increased the expression of specific genes including nestin, ß-tubulin III, MAP2 and Olig2. In addition, immunohistochemical analysis confirmed expression of specific neural-related proteins including MAP2, GFAP and Olig2 in irradiated cells. ROS generation significantly increased following green light irradiation which in turn has activated the MAPK signaling pathway, resulting in the differentiation of hUCMs into neurons and glial cells, confirmed by western blot analysis of MAPK-related pathway. Taken together, our results suggest that the green LED irradiation, alone and in combination with RA, via ERK 1/2, JNK and p38 phosphorylation improves differentiation of hUCMs into neural lineage. Other mechanisms and inducers to enhance differentiation phenomena in vitro and in vivo should be investigated to determine the most appropriate strategy for therapeutic purposes.

Psychometric properties of the physical environment problems and barriers scale in older adults' homes using an ergonomic approach.

BACKGROUND: As older adults prefer to live in their homes, it is of paramount importance to examine the adaptation of the environment to the older adults' capabilities. OBJECTIVE: The aim of this study was to develop and evaluate psychometric properties of a scale to measure physical environment problems and barriers in older adults' homes using an ergonomic approach in Iran. METHODS: This mixed-method investigation was conducted in two stages in Yazd, Iran. The primary 71-item version of the questionnaire was developed according to qualitative findings and a thorough review of the literature. Then the psychometric characteristics, including face, content, construct validity, were assessed. Content validity was also assessed using CVI and CVR. Finally, its reliability and construct validity were confirmed by composite reliability (CR), Fornell-Larker matrix, and confirmatory factor analysis (CFA) using Smart PLS software version 3. RESULTS: The face validity of the developed scale was acceptable, and the mean scores of CVI and CVR were 0.78 and 0.84, respectively. The preliminary draft of the scale was categorized into seven dimensions. Factor validity and reliability were confirmed by acceptable factor loadings, and desirable realms of composite reliability (>0.7) average variance extracted (>0.5). The cross-loading method and the Fornell-Larker matrix were used to evaluate the divergent validity of the scale, and the results confirmed its acceptable fit. CONCLUSIONS: The findings indicated that reliability reached acceptable values, and different aspects of validity were almost confirmed. Accordingly, the questionnaire was to measure physical environment problems and barriers in older adults' homes; however, it requires further validation for future use in other contexts.

Quantification of the impact of factors affecting the technical performance of operating room personnel: Expert judgment approach.

Incorrect assessment of the performance shaping factors (PSFs), especially in health care systems, may lead to irreversible consequences such as death. The current study aimed to adapt PSFs taxonomy given in standardized plant analysis risk human reliability analysis (SPAR-H) technique to surgical context. PSFs taxonomy of the SPAR-H technique was revised, and more contextspecific definitions to surgical context were suggested. Step-wise weight assessment ratio analysis (SWARA) and eleven-digit numerical scale were used for quantification of the weight and negative influence rate of the PSFs during surgical processes, respectively. Nine PSFs were proposed following the SPAR-H taxonomy. The order of the importance of the PSFs was quietly conflicting in terms of weight and negative influence rate. From the perspective of experts, fatigue and threat stress were assessed as the most important PSFs in terms of both weight and negative influence rate. Current study has offered a domain-based understanding of the PSFs, particularly in the surgical context. Results of this study could be used to evaluate human error behaviors during the performance of tasks in the operating room. Moreover, these results could be used for improving patient safety programs in health care systems.

Identifying barriers and problems of physical environment in older adults' homes: An ergonomic approach.

BACKGROUND: The main purpose of ergonomics is environment adaptation to humans, and the root cause of the barriers and problems of the older adults is the mismatch between the home environment and their limitations. OBJECTIVE: The present study aimed to identify and explain physical environment barriers and problems among older adults' homes in Yazd, Iran. METHODS: This qualitative study was conducted as conventional content analysis. In total, 53 participants including 36 older adults and 17 caregivers were enrolled in the study. The participants were selected using convenience and purposive sampling methods, while the data collection method was a semi-structured interview. The interviews were recorded and transcribed, and then analyzed using MAXQDA11 software. RESULTS: Following data analysis, 268 initial codes were extracted. They were classified into three major categories and 31 sub categories. The main categories are "barriers and problems associated with older adults' sensory limitations," "barriers and problems associated with older adults' motor limitations," and "barriers and problems associated with older adults' cognitive limitations." CONCLUSIONS: Although the data collected from the older adults and their caregivers are in many cases similar, caregivers can provide reasons for the barriers and problems as well as solutions better than the older adults. The data also indicate that most of the problems and barriers are related to motor limitations.

Serum microRNA-33 levels in pre-diabetic and diabetic patients.

Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and abnormal insulin secretion. MicroRNAs are small, non-coding RNAs that are able to affect cell biological functions and act as biomarkers for some diseases such as DM. In current study, we measured serum miR-33 in three groups (n = 15) as follows; non-diabetic control, pre-diabetic, and DM patients. Real-time PCR method was used to quantify miR-33 expression. miR-33 expression was significantly increased in pre-diabetic subjects compared to other two groups (p < 0.001). FBS (p < 0.001), insulin (p < 0.001), HOMA-IR (p < 0.001), and TG (p = 0.026) were higher in diabetic subjects than the other two groups. In people that had high physical activity, the number of diabetic subjects were zero and most of them were in pre-diabetic group (p = 0.019). Serum miR-33 level significantly and positively correlated with pre-diabetic state (B = 2.67, p = 0.000), Sex (B = 1.03, p = 0.025), and FBS (B = 0.04, p = 0.036) and also miR-33 was significantly and negatively correlated with HOMA-IR (B = - 1.58, p = 0.04). These findings support the possible role of miR-33 to monitor pre-diabetes onset and progression. It needs to be evaluated in future studies with high number of participants to clarify its mechanism and diagnostic viability.

Can Estradiol and Ghrelin Play a Protective Role in Epithelial Ovarian Cancer Incidence in Postmenopausal Women?

OBJECTIVE: The present study aimed to investigate the association between estradiol, n-octanoylated, des-octanoylated, total ghrelin, and ghrelin/des-octanoylated ghrelin ratio levels along with pathological parameters and epithelial ovarian cancer (EOC) odds in postmenopausal women. MATERIALS AND METHODS: A case-control study was carried out on 45 patients with EOC and 33 age-matched postmenopausal women as the control group. Plasma levels of estradiol, n-octanoylated, des-octanoylated, and total ghrelin were measured by ELISA method. RESULTS: Estradiol's plasma levels were significantly higher in patients with EOC than in control women (p <0.001). Although the ratio levels of n-octanoylated, des-octanoylated, total ghrelin, and ghrelin/des-octanoylated ghrelin were not associated with EOC in logistic regression models, estradiol levels were significantly related to the increase in EOC odds (OR: 1.083, 95% CI: 1.037-1.13, p <0.001). However, estradiol levels in the two first quartiles (Q1, Q2) were associated with decreased odds of EOC (OR: 0.011, 95% CI: 0.001-0.118, p <0.001, and OR: 0.030, 95% CI: 0.003-0.284, p = 0.002, respectively). For those patients in the third quartile of plasma des-octanoylated and total ghrelin compared to those in the highest (Q4), the multivariate odds ratios of EOC were respectively 0.192 and 0.25. CONCLUSION: In conclusion, higher concentrations of des-octanoylated and total ghrelin might be associated with the decreased EOC odds. Furthermore, the findings suggest that high levels of estradiol might be a potential odds factor in EOC, however, lower estradiol levels may have a protective effect on EOC development.

Pesticide exposure and related health problems among family members of farmworkers in southeast Iran. A case-control study.

BACKGROUND: Pesticides used in agriculture are some of the most common pollutants in the world. This study aimed to investigate the effects of Organophosphorus Pesticides (OPPs) and Organochlorine Pesticides (OCPs) on the families of farmworkers in the southeast of Iran. METHODS: In the present case-control study, 141 family members of farmworkers (as the case group) and 59 family members of non-farmworkers (as the controls) were recruited. Serum levels of OCPs such as α-HCH, ß-HCH, γ-HCH, 2,4-DDE, 4,4-DDE, 2,4-DDT, and 4,4-DDT were determined. In addition, erythrocyte acetylcholinesterase (AChE) activity, malondialdehyde (MDA), total antioxidant capacity (TAC), protein carbonyl (PC), nitric oxide (NO) serum levels, arylesterase activity of paraoxonase 1 (PON-1), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activity were determined in all participants. Furthermore, distance to farmlands, education, crops, type, and the number of consumed fruits were evaluated for each individual separately. RESULTS: The erythrocyte AChE activity and serum activities of GPx, SOD, and PON-1 and TAC levels were significantly decreased, whereas the concentration of MDA, PC, NO, and seven OCPs were significantly increased in the farmworkers' families as compared to the controls. Spearman correlation and linear regression suggest that OCPs increase the oxidative stress in farmworkers' family members. Moreover, distance, education, farming precedence, products, and ventilation had significant effects on the OCP levels and increased the odds ratio of OCP levels in farmworkers' families. CONCLUSION: With regards to the data obtained in this study, it was revealed that OCPs as illegal pesticides and OPPs were higher than expected in the farmworkers' family members. Furthermore, exposure to OCPs and OPPs, apart from the other effects on the body, leads to oxidative stress (OS) that may cause serious diseases in the exposed populations.

Aging is associated with loss of beneficial effects of estrogen on leptin responsiveness in mice fed high fat diet: Role of estrogen receptor α and cytokines.

Aging causes changes in body composition and energy balance. Estrogen plays an important role in body's metabolism. The aim of this study was to determine whether estrogen has beneficial effects on leptin responsiveness in aged mice. Young 4 months and aged 19-21 female mice fed High Fat Diet (HFD) or Standard Diet (SD) for 12 weeks and following received estrogen for 4 weeks. Responsiveness to leptin was compared by measuring energy balance parameters. Results showed that HFD caused weight gain compared to SD in young, but had no effect on aged animals. Estrogen reduced body weight, energy intake and visceral fat in young, while none of these parameters was affected in aged animals. Although there was leptin sensitivity in aged compared to ovariectomized animals, estrogen only improved the sensitivity of young to leptin. Estrogen prevented increase in TNF-α and a decrease in IL-10 in HFD young and aged animals. Response to estrogen depended on age, and estrogen increased leptin sensitivity only in young animals. Determining the exact mechanism of this action is suggested in future studies.

IRAK inhibitor can improve insulin sensitivity in insulin-resistant mice fed with a high-fat diet.

Background: Obesity and the inflammation associated with it, play a key role in the development of insulin resistance through the release of inflammatory cytokines and free fatty acids and the stimulation of toll-like receptors (TLR). Interleukin-1 receptor-associated kinase (IRAK), which mediates the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, is an important molecule in TLR signaling. The NF-κB pathway can reduce insulin efficacy by increasing the expression of proinflammatory cytokines. There is no safe inhibitor for the NF-κB pathway, and for this reason, the upper mediator of this pathway was selected for investigation. Objectives: To determine the effects of an IRAK inhibitor on insulin resistance and serum biochemical factors in high-fat-fed insulin-resistant mice. Methods: Insulin resistance was developed in C57BL/6J mice by 12 weeks of a high-fat diet. Subsequently, the IRAK 1/4 inhibitor 1-(2-(4-morpholinyl)ethyl)-2-(3-nitrobenzoylamino)benzimidazole (IRAKi)/or pioglitazone, or both, were administered for a further 2 weeks. After 12 h fasting, blood and tissue samples were collected, insulin and glucose levels were assayed, and the homeostatic model assessment was used to quantify insulin resistance (HOMA-IR). Results: The IRAKi decreased blood glucose levels significantly (253 ± 14.3 mg/dL vs 390.1 ± 16.6 mg/dL) and increased insulin sensitivity compared with untreated controls. However, we did not find a synergistic effect of IRAKi with pioglitazone in increasing insulin sensitivity. Conclusion: IRAKis can increase insulin sensitivity and their efficacy is comparable to pioglitazone. However, combined administration of pioglitazone and IRAKi had no synergistic effect compared with monotherapy.

Serum levels of Organochlorine Pesticides and Breast Cancer Risk in Iranian Women.

Breast cancer is a multifactorial disease and its etiology is linked to multiple risk factors. There are shreds of controversial evidence that exposure to organochlorine pesticides (OCPs) are important in the etiology of breast cancer. The present study aimed to determine the circulating levels of OCPs in patients with breast tumors in Southeastern of Iran. This case-control study included 27 patients with malignant breast tumors (MBT), 31 patients with benign breast tumors (BBT), and 27 healthy women as a control group. Serum OCPs levels, including α-hexachlorocyclohexane (α-HCH), ß-HCH, γ-HCH, 2,4-dichlorodiphenyltrichloroethane (2,4-DDT), 4,4-DDT, 2,4-dichlorodiphenyldichloroethylene (2,4-DDE), and 4,4-DDE, were measured using gas chromatography. Our data revealed significantly higher concentrations of 2,4-DDT in MBT and BBT groups compared with control ones (P < 0.001 for both comparisons). Patients with breast cancer suffered significantly higher accumulation levels of 4,4-DDE compared with control subjects (P = 0.04). Significant correlations were found among organochlorine compounds with each other in both patients' groups. There was a significant positive correlation between body mass index and serum levels of 2,4-DDT in BBT group (r = 0.407, P = 0.02). The present findings suggest that the serum levels of 4,4-DDE and 2,4-DDT are associated with an increase in the risk of breast cancer in Southeastern women of Iran.

Organochlorine and organophosphorus pesticides and bladder cancer: A case-control study.

BACKGROUND: Exposure to pesticides is associated with an increase in the incidence of cancer. We aimed to investigate the association of serum organochlorine pesticides (OCPs) and organophosphorus pesticides (OPs) levels and GSTM1/GSTT1 gene polymorphism with bladder cancer (BC). METHODS: This study was performed on 57 patients with BC and 30 controls (C). Acetylcholinesterase (AChE) activity, arylesterase activity of paraoxonase-1 (ARE), total antioxidant capacity (TAC), and malondialdehyde (MDA) levels were determined in serums of all participants. Genomic DNA was extracted using the salting out method and GSTM1/GSTT1 gene polymorphisms were examined by multiplex polymerase chain reaction assay. Measurement of OCPs (α-hexachlorocyclohexane [α-HCH], ß-HCH, γ-HCH, 2,4-dichlorodiphenyltrichloroethane [2,4-DDT], 4,4-DDT, 2,4- dichlorodiphenyldichloroethylene [2,4-DDE], and 4,4-DDE) in serum was carried out using an FID-equipped gas-chromatography system. RESULTS: AChE activity was significantly lower, ARE activity and TAC were declined but it was not statistically significant, however, α-HCH, γ-HCH, 4,4-DDE, 2,4-DDT, and 4,4-DDT pesticides, and MDA were significantly higher in BC patients compared with the control subjects. Also, a positive correlation was found between the number of smoked cigarettes and the years of smoking with BC development. There was no association between GSTM1/GSTT1 gene polymorphisms and OCPs in BC patients. CONCLUSION: Due to the higher levels of some OCPs in the BC patients, along with the reduction in AChE activity and increased MDA levels, it may be concluded that OCPs and OPs play an important role in the induction of BC in southeastern Iran.

Organochlorine and organophosphorous pesticides may induce colorectal cancer; A case-control study.

OBJECTIVES: Among the numerous agents, genetic factors and environmental elements such as pesticides have an important role in colorectal cancer (CRC) incidence. The present study aimed to investigate the probable-role of some organochlorine pesticides (OCPs) and organophosphorous pesticides (OPPs) in patients with CRC. METHODS: In this case-control study, 42 patients with CRC and 30 healthy subjects were selected. The serum levels of some OCPs (α-HCH, ß-HCH, γ-HCH, 2,4 DDE, 4,4 DDE, 2,4DDT and 4,4DDT) were measured by gas chromatography (GC) method. Serum levels of malondialdehyde (MDA), and total antioxidant capacity (TAC) as well as the enzyme activity of acetylcholinesterase (AChE) and arylesterase activity of Paraoxonase-1 (PON-1) were evaluated in all participants. The methylation specific PCR (MSP) assay was used for determining the methylation status of CpG island of p16 and MGMT genes in CRC patients. RESULTS: The mean serum levels of each OCPs were significantly higher in the patient group compared to the control group (P < 0.001). The AChE and arylesterase activity of PON-1 in the patient group were significantly lower than the control group (P < 0.001). The mean serum levels of MDA and TAC in the serum of the patient group were significantly higher than the control group (P < 0.001 and P < 0.002, respectively). The current findings demonstrated significantly hypermethylation of p16 promoter in CRC patients. CONCLUSION: Regarding the higher levels of OCPs in CRC patients, along with hypermethylation of the p16 promoter gene, diminishing in AChE and PON-1 activity and increasing in oxidative stress factors, the role of OCPs and OPPs in the CRC progression in the South-East of Iran may be assumed.

Epigenetic modulation of BRCA-1 and MGMT genes, and histones H4 and H3 are associated with breast tumors.

Aberrant patterns in promoter methylation of tumor-suppressor genes and posttranslational modifications of histone proteins are considered as major features of malignancy. In this study, we aimed to investigate promoter methylation of three tumor-suppressor genes (BRCA-1, MGMT, and P16) and three histone marks (H3K9ac, H3K18ac, and H4K20me3) in patients with breast tumors. This case-control study included 27 patients with malignant breast tumors (MBT) and 31 patients with benign breast tumors (BBT). The methylation-specific PCR was used for determining promoter methylation of BRCA-1, MGMT, and P16 genes. Western blot analysis was performed to detect histone lysine acetylation (H3K9ac and H3K18ac) and lysine methylation (H4K20me3). BRCA-1 promoter methylation was detected in 44.4% of the MBT whereas this alteration was found in 9.7% of BBT (P = 0.005). The Kaplan-Meier analysis indicated that hypermethylation in BRCA-1 promoter was significantly associated with poor overall survival of patients with breast cancer (P = 0.039). MGMT promoter methylation was identified in 18.5% of MBT and 0.0% of the BBT (P = 0.01). The frequency of P16 promoter methylation was 25.8% in BBT and 11.1% in MBT (P = 0.12). As compared with BBT, MBT samples displayed the aberrant patterns of histones marks with hypomethylation of H4K20 and hypoacetylation of H3K18 (P = 0.03 and P = 0.04, respectively). There was a negative significant correlation between H3K9ac levels and tumor size in MBT group (r = -0.672; P = 0.008). The present findings suggest that promoter hypermethylation of MGMT and BRCA-1 genes along with alterations in H3K18ac and H4K20me3 levels may have prognostic values in patients with breast cancer. Moreover, the detection of these epigenetic modifications in breast tumors could be helpful in finding new methods for breast cancer therapy.

Inhibitor of Interleukin-1 Receptor-associated Kinases 1/4, Can Increase the Sensitivity of Breast Cancer Cells to Methotrexate.

Breast cancer is the most common type of cancer among women. Chemotherapy is one of the main methods of breast cancer treatment, but this method is increasingly affected due to drug resistance. One of the newly discovered factors associated with drug resistance in cancer cells is interleukin receptor-associated kinase 1 (IRAK1). The aim of this study was to investigate the relationship between IRAK1 inhibition and sensitivity to methotrexate (MTX). Effects of various concentrations of MTX and constant concentration (1µg/ml) of IRAK1/4 inhibitor was examined on MCF-7, BT-20, BT-549, MB-468 cell lines. Cell viability was examined by water soluble tetrazole -1, and cell apoptosis by flow cytometry. The expression of IRAK1 and BCRP genes was also assessed by real-time PCR method. IRAK1 inhibitor decreased IC50 in all examined cell lines, but the most prominent effect was observed in MB-468. 72 h incubation of cell lines with IRAK inhibitor and MTX, significantly increased the annexin-V and annexin-V/7AAD positive cells, suggesting an apoptotic effect of IRAK on all examined breast cancer cell lines. RT-qPCR test results showed that the IRAK inhibitor had no effect on the expression of BCRP at any time. Our results showed that IRAK inhibitor can increase the chemosensitivity of breast cancer cell lines without effect on BCRP mRNA expression. IRAK inhibitor in combination with MTX can induce apoptosis in breast cancer cell lines.

Downregulation of Matrix Metalloproteinases 2 and 9 is Involved in the Protective Effect of Trehalose on Spinal Cord Injury.

Upregulation of matrix metalloproteinases (MMPs), in particular MMP-2 and MMP-9 contributes to secondary pathogenesis of spinal cord injury (SCI) via promoting inflammation. Recently, we have reported that trehalose suppresses inflammatory responses following SCI. Therefore, we investigated the effect of trehalose on MMP-2 and MMP-9 expression in SCI. A weight-drop contusion SCI was induced in male rats. Then, the animals received trehalose at three doses of 10 (T10), 100 (T100) and 1000 (T1000) mM intrathecally. MMP-2 and MMP-9 transcripts were then measured in damaged spinal cord at 1, 3 and 7 days after trauma, and compared with vehicle and sham groups. Additionally, behavioral analysis was conducted for 1 week using Basso-Beattie-Bresnahan (BBB) locomotor rating scale. Our data showed an early upregulation of MMP-9 at 1 day post-SCI. However, MMP-2 expression was increased at 3 days after trauma. Treatment with 10 mM trehalose significantly reduced MMP-2 expression in 3 and 7 days (P< 0.01) and MMP-9 expression in 1, 3, and 7 days (P< 0.05) post-damage compared with vehicle. Nonetheless, downregulation of both MMPs was not observed in T100 and T1000 groups. In addition, T10 group showed more rapid recovery of hind limb strength compared with T100 and T1000 groups. We propose that the neuroprotective effect of low dose trehalose is mediated by attenuation of MMP-2 and MMP-9 expression.

Inhibition of Interleukin-1 Receptor-Associated Kinases 1/4, Increases Gene Expression and Serum Level of Adiponectin in Mouse Model of Insulin Resistance.

Insulin resistance is a feature of most patients with type 2 diabetes mellitus. Epidemiological evidence suggest a correlation between inflammation and insulin resistant states such as obesity, but the underlying mechanisms are largely unknown. Interleukin-1 receptor-associated kinases (IRAK) play a central role in inflammatory responses by regulating the expression of various inflammatory genes in immune cells. This study was aimed to investigate the effect of IRAK inhibitor on gene transcription and serum concentration of adiponectin in insulin-resistant mice. Experimental mice were randomly divided into 6 groups: the healthy control group was fed a regular chow diet while other groups were fed with a high-fat diet for 12 weeks. After this period, the animals were treated with IRAK inhibitor, pioglitazone, both IRAK and pioglitazone, and DMSO, for two weeks. Adiponectin gene expression level was analyzed by real-time PCR. Additionally, serum adiponectin levels were measured by ELISA. Homeostasis model assessment-adiponectin (HOMA-AD) as an insulin sensitivity index was calculated. IRAK inhibitor and pioglitazone increased significantly the expression of adiponectin gene. Also, adiponectin concentration in the control group (9.67±1.1 µg/ml) increased to 25.34±2.04 µg/ml in pioglitazone treatment group. IRAK inhibitor also increased adiponectin concentration (18.24±1.53 µg/ml) but did not show a synergistic effect with pioglitazone when administered simultaneously (26.66±2.5 µg/ml). HOMA-AD was 0.33±0.04 in pioglitazone treated group, 0.6±0.13 in IRAK inhibitor group, and 0.31±0.03 in animals that received IRAKi and pioglitazone. Our findings suggest that increased adiponectin secretion from adipose tissue mediated by IRAK inhibitor may increase the insulin sensitivity in an animal model of insulin resistance.

Antihyperglycemic Effect of Rosa Damascena is Mediated by PPAR.γ Gene Expression in Animal Model of Insulin Resistance.

Insulin resistance is a condition in which insulin signaling and action are impaired in insulin sensitive tissues and result in hyperglycemia, hyperlipidemia, and type 2 diabetes mellitus. Our previous studies have shown that Rosa damascena has antihyperglycemic effects on diabetic and normal rats. Therefore, we conducted a study to evaluate the effect of this medicinal plant on insulin sensitivity in rats. This study was performed on high fructose diet insulin resistant rats and pioglitazone, an insulin sensitizing drug, was used as a positive control. Insulin resistance was developed in animals by high fructose diet within six weeks. Then, Rosa damascena extract and pioglitazone were administered by gavage for two weeks and results were compared with two control groups. After treatment period, serum glucose, insulin, adiponectin, triglyceride, and cholesterol were assayed in fasting state. Plasma free fatty acid profile was analyzed by GC. Liver PPAR.γ and muscle GLUT.4 gene expressions were assessed by real time PCR and western blotting. Animals were treated with rosa damascena extract showed levels of insulin (42 ± 2.7 pmol/L). adiponectin (5.6±0.17 µg/mL). glucose (129±4.7 mg/dL). and triglyceride (75 ± 9 mg/dl) which were significantly improved as compared with control group insulin (137 ± 34 pmol/L), adiponectin (3.9±0.15 µg/mL). glucose (187±15 mg/dL). and triglycerides (217±18 mg/dL). PPARγ protein level was also significantly increased in Rosa damascene treated group. Our results demonstrated that rosa damascena extract has useful effects on insulin resistant animals and by increasing insulin sensitivity can be considered as a potential agent in control of diabetes.